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3-trifluoromethyl-2,5-diazabicyclo[2.2.1] heptane derivant and preparation method thereof

A technology of trifluoromethyl and diazabicyclo, which is applied in the field of 3-trifluoromethyl-2,5-diazabicyclo[2.2.1]heptane derivatives and its preparation, can solve the problem of poor water solubility of compounds, space Structural extension limitations, etc.

Inactive Publication Date: 2011-08-31
上海药明康德新药开发有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems that the current 2,5-diheterobicyclo[2.2.1]heptane bridged ring compound is limited in the extension of the space structure and the compound has poor water solubility

Method used

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  • 3-trifluoromethyl-2,5-diazabicyclo[2.2.1] heptane derivant and preparation method thereof
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  • 3-trifluoromethyl-2,5-diazabicyclo[2.2.1] heptane derivant and preparation method thereof

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specific Embodiment approach ： Embodiment ， Embodiment 。 Embodiment 1

[0067] Specific embodiments: Examples are given to describe the present invention in detail, but the present invention is not limited to these examples. Example 1: Preparation of 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane

[0068]

[0069] Steps:

[0070] 2-Benzyl-3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane V (2.0 g, 5.62 mmol) in methanol (20 mL) 10% palladium carbon (50 mg) was added to the solution, hydrogen gas (1 atm) was introduced, and the mixture was stirred at room temperature (20-30° C.) for 12 hours. After filtration, the reaction solution was concentrated to obtain 1.35 grams of 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane VI (90% yield) (wherein petroleum ether acetic acid ethyl ester as eluent).

[0071] HNMR (CDCl 3 )δ: 4.68(s, 1H), 3.79-3.71(m, 1H), 3.70-3.61(m, 1H), 3.36-3.28(m, 1H), 3.24-3.18(m, 1H), 2.25(d, J=12.6Hz, 1H), 1.82(d, J=12.6Hz, 1H), 1.40(s, 9H).

Embodiment 2

[0072] Example 2: Preparation of 2-methyl-3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane

[0073]

[0074] Steps:

[0075] 3-Trifluoromethyl-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane VI (100 mg, 0.376 mmol), paraformaldehyde (120 mg, 0.376 mmol) , trifluoroacetic acid (0.1 ml) and tetrahydrofuran (10 ml) were stirred overnight (12-16 hours) at room temperature (20-30° C.). Then add methanol (2 ml), sodium borohydride (0.18 g, 4.52 mmol) and react for 0.5 hours, concentrate the reaction solution, dissolve in water (20 ml), extract with ethyl acetate (3*6 ml), and dry the organic phase Concentrated crude product. The crude product obtained 89 mg of 2-methyl-3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane VI (yield 85% ) (with petroleum ether ethyl acetate as eluent).

[0076] HNMR (CDCl 3 )δ: 4.39(s, 1H), 3.73(s, 1H), 3.70-3.61(m, 1H), 3.36-3.28(m, 1H), 3.24-3.18(m, 1H), 2.54(s, 3H) , 2.25(d, J=12.6Hz, 1H), 1.82(...

Embodiment 3

[0077]Example 3: Preparation of 2-methyl-3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane

[0078]

[0079] Steps:

[0080] Under nitrogen protection, a suspension of anhydrous tetrahydrofuran (3 ml) containing sodium hydrogen (60% content, 30 mg, 0.752 mmol) was stirred at 0°C for 0.5 hours, and then 1 ml of 3-trifluoromethyl- 5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane VI (100 mg, 0.376 mmol) in anhydrous tetrahydrofuran solution, continue to stir at 0°C for 0.5 hours, then slowly add iodine Methane (64 mg, 0.451 mmol) or methyl bromide (42 mg, 0.451 mmol), and the reaction solution was stirred overnight (12-16 hours) at room temperature (20-30° C.). After the reaction was completed, 1 ml of water was added dropwise under ice-water cooling to quench the reaction, the reaction solution was concentrated, dissolved in water (10 ml), extracted with ethyl acetate (3*20 ml), and the organic phase was dried and concentrated to obtain a crude produ...

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Abstract

The invention discloses a 3-trifluoromethyl-2,5-diazabicyclo[2.2.1] heptane derivant and a preparation method thereof, mainly aiming to solve the technical problems that bridged compounds with structure of 2,5-diazabicyclo[2.2.1] heptane are restrained in extension of a space structure, and the compounds have poor water solubility. The chemical structural formula is as follows in the specification, wherein X is NR1 or O, R1 is a functional group or amino-substituted protective group, and is selected from one of H, C1-10 linear-chain or substituent-side-chain-containing alkyl, benzyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, tertiarybutoxy carbonyl, carboxybenzyl, alkylacyl, aroyl, alkylsulfonyl or aryl sulfonyl, and R2 is a functional group or amino-substituted protective group, and is selected from one of H, C1-10 linear-chain or substituent-side-chain-containing alkyl, benzyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, carboxybenzyl, alkylacyl, aroyl, alkylsulfonyl or aryl sulfonyl.

Description

Technical field: [0001] The present invention relates to 3-trifluoromethyl-2,5-diazabicyclo[2.2.1]heptane derivatives, especially 2-substituted-3-trifluoromethyl-2,5-diazabicyclo[2.2 .1] Heptane derivatives or 3-trifluoromethyl-5-substituted-2,5-diazabicyclo[2.2.1]heptane derivatives or 2,5-disubstituted-3-trifluoromethyl -2,5-diazabicyclo[2.2.1]heptane derivatives or 5-substituted-3-trifluoromethyl-2-oxa-5-azabicyclo[2.2.1]heptane derivatives and Preparation. Background technique: [0002] Bridged ring compounds are a class of molecules with special structures, which can effectively link and integrate key pharmacophore units into their rigid structures to form molecules with special spatial configurations / conformations, which can match different biological macromolecules in vivo Many bridged ring compounds have different biological activities, so they have broad application value, especially as template compounds in the process of drug research. Bridged ring compounds co...

Claims

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Application Information

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IPC IPC(8): C07D487/08C07D491/08
CPCY02P20/55
Inventor 张永明彭宣嘉胡利红叶俊涛董径超吴颢马汝建陈曙辉
Owner 上海药明康德新药开发有限公司
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